Significance Vaccination of HIV-infected pregnant women has the potential to prevent orreduce HIV transmission from a mother to her infant by lowering maternal virus load and/or by enhancing the levels or specificities of antiviral antibodies transferred to the fetus transplacentally. Vaccination may be less costly than antiviral drugs and thus, more economically feasible to use in developing nations. Objectives Infection of newborn rhesus macaques with simian immunodeficiency virus is a well-established model for pediatric HIV infection and AIDS. This study evaluated whether an SIV vaccine given to pregnant macaques could generate transplacental antiviral antibodies that would protect neonates against oral SIV infection. Results Four pregnant rhesus macaques were immunized twice intramuscularly during pregnancy with whole-inactivated SIV in adjuvant. After boosting, dams produced high titer SIV-specific serum antibodies which were transferred to their infants. Infants were inoculated orally with a high dose of SIV within 3 days of birth. This oral dose of SIV infected four naive neonatal rhesus; all four developed high virus levels in peripheral blood and fatal immunodeficiency by 12-26 weeks pi. In contrast, only one of the four neonates with maternal SIV-specific antibodies was infected after oral SIV inoculation and developed fatal simian AIDS (in ~3 months). Thus, vaccination of dams with whole-inactivated SIV protected three of four infants against oral SIV infection, but did not delay disease in the neonate that became SIV-infected. These results suggest that an HIV vaccine that could generate high levels of anti-HIV antibodies in HIV-infected pregnant women might reduce the risk of HIV transmission to infants during the birth process or by breast-feeding. Future Directions Immunogenicity of anti-SIV vaccine regimens will be compared in rhesus newborns that have (1) no anti-SIV antibodies or, (2) passively acquired anti-SIV antibodies to determine whether passive antiviral antibodies interfere with neonatal vaccination against SIV. KEYWORDS pediatric simian AIDS, oral SIV transmission, perinatal HIV transmission, immunization in pregnancy